In the past decade the use of the stimulant methamphetamine (MA) has increased in the general population, with worldwide abuse of amphetamines surpassing that of cocaine and opiates combined. In parallel with the explosion of MA use around the globe, MA is steadily becoming a drug widely abused by patients with schizophrenia (SZ). Although many drugs of abuse can exacerbate clinical symptoms in SZ patients thus increasing the burden on the mental health system, MA, which acts preferentially on the DA system and produces psychotic symptoms similar to SZ, may be the most damaging drug to plague this psychiatric population in decades. Despite the fact that MA is extremely neurotoxic to the human brain via multiple neurotoxic mechanisms and with a duration of action that can be at least ten times that of cocaine, comorbid MA use has received relatively little scientific investigation. The goal of this proposal is to generate a neural signature of comorbid MA abuse, characterize cognitive function in SZ patients who abuse MA and link neural and cognitive function to changes in clinical symptomatology that occur following MA abuse. In order to accomplish the goals of this R01 we will obtain fMRI data in targeted brain regions in conjunction with computerized measures of cognition and assessments of clinical symptoms. Five groups will be studied: 1) SZ patients with comorbid MA abuse (SZ+MA); 2) SZ patients with comorbid cannabis abuse (SZ+MJ); 3) SZ patients without comorbid substance abuse (SZ); 4) abstinent MA abusers (MA); and 5) matched controls (CTL). Four regions will be examined: 1) dorsolateral prefrontal cortex (DLPFC); 2) Rostral; and 3) Caudal anterior cingulate cortex (rACC and cACC); as well as 4) a control region the primary visual cortex (PVC). Three of these structures (DLPFC, rACC and cACC) receive rich dopaminergic input and are thought to be key regions within the neural circuitry associated with both addiction and SZ. The resulting data will allow for the differentiation and identification of unique neural and cognitive correlates of MA abuse and SZ. The detection of physiological differences in SZ who abuse drugs versus those SZ who do not will provide an objective measure of the neural correlates of comorbid substance abuse. As observed brain activation, cognitive deficits and substance use patterns have been shown to be linked to specific therapies; this study will generate predictive information about who might respond to specific forms of treatment intervention. Further studies can then be designed to test treatment outcome. The data generated by this research program will provide a multi-dimensional understanding of substance abuse and comorbid addiction and will have direct applications to neurobiological models of addiction and treatment applicable to all drugs of abuse. PUBLIC HEALTH RELEVANCE Comorbid substance abuse in patients with schizophrenia is a major health concern. In parallel with the explosion of methamphetamine (MA) abuse in the general population, many schizophrenia patients are also abusing this highly addictive stimulant drug. The goal of this proposal is to use functional brain imaging and behavioral measures to examine the effect of co morbid MA abuse in schizophrenia patients. This approach will generate a multi-dimensional understanding of substance abuse and comorbid addiction with direct applications to current models of addiction and treatment applicable to all drugs of abuse.